DESCRIPTION (from applicant's abstract): This proposal will investigate the contribution of nuclear transport activities of Vpr and Vpx proteins to primate lentiviral pathogenicity. In vitro studies will be used to identify domains required for nuclear localization of HIV-1 Vpr and SIV Vpx and for association of Vpr and Vpx with viral reverse transcription complexes, and to characterize the pathway through which nuclear localization is directed and examine the phenotype of nuclear import mutants in macrophage infection. In vivo studies in rhesus macaques will be used to examine the relative fitness of selected SIV Vpx mutants, which are impaired in nuclear import. The specific aims are: 1) identify effector domains for nuclear localization of HIV-1 Vpr and SIV Vpx and for association of Vpr/Vpx with viral reverse transcription complexes; 2) characterize the pathway through which nuclear localization of Vpr/Vpx proteins is directed and identify the potential role of bridging proteins in the interaction of Vpr/Vpx with the nuclear import apparatus; 3) examine the phenotype of nuclear import mutants of HIV-1 and SIV in macrophage infection; 4) examine the relative in vivo fitness of SIV Vpx mutants which are altered in nuclear import. It is expected that these studies will more fully define the contribution of nuclear import activities of Vpr and Vpx to virus replication in vitro and in vivo.